This project is a comprehensive, multidisciplinary effort to understand the natural history and modes of transmission of viruses and other infectious agents that are associated with cancer. With numerous intramural and extramural laboratory, clinical, and epidemiologic collaborators, and a core of prospective cohort and case-control studies, the effort is focused on human immunodeficiency virus (HIV), human T-lymphotropic virus types I and II (HTLV-I/-II), hepatitis C virus (HCV), and Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8 or HHV-8). The Second Multicenter Hemophilia Cohort Study (MHCS-II) enrolled and completed prospective follow-up of more than 2500 HCV-exposed persons with hemophilia. Testing of the cohort with newly developed Taq-Man PCR assays for detection and quantification of HCV and HIV RNA was also completed. A public website was established (https://mhcs-ii.rti.org) with background information and data analysis procedures. Among HIV-uninfected participants, spontaneous clearance of HCV was found to be associated with infection at a very young age and in relatively recent calendar years. In collaboration, AIDS progression rate was related to differences in several genes related to immunity. The hepatitis C virus (HCV) epidemic in the U.S. hemophilia population was reconstructed, revealing that most infections occurred prior to use of clotting factor concentrates. Spontaneous clearance of HCV infection was shown to be greatly increased with hepatitis B virus (HBV) co-infection. In addition, among hemophiliacs without HIV, HCV clearance also was clustered in families and increased with early age at infection. An HBV viral load assay was developed, and clearance of HBV was related to variants in the IL-18 gene. Progression of HIV/AIDS was shown to be associated with variants in several immunity-related genes (CUL5, cyclophilin A, TSG101, and HLA/KIR), and new methods were developed to analyze these complex relationships. A four-year case-control study of classical (non-AIDS) Kaposi sarcoma and KSHV infection thorughout the island of Sicily (where cKS and KSHV are endemic) was completed. Classic (non-AIDS) Kaposi sarcoma (KS) risk was shown to be related to variants in cytokine-pathway genes, as well as to subtle hematologic abnormalities and to elevated blood levels of the KS-associated herpes virus (KSHV, also known as human herpes virus 8). Risk of KSHV also differed with cytokine gene variants, and these associations appeared to differ by gender. Field work on a new classic KS case-control study was completed, and preliminary analysis confirmed that KS risk was significantly reduced with current cigarette smoking.KS transdermal nicotine trial A 15-week randomized clinical trial was completed, showing that use of transdermal patches to directly deliver nicotine to classic KS lesions was neither harmful no beneficial.Among children with HTLV-I infection, antibody titer was found to increase for the first year after infection. HTLV-I proviral load increased for an additional year, but only in children with eczema, which may be an indicator of higher risk of disease (adult T-cell leukemia/lymphoma and tropical spastic paraparesis) during adulthood. Among HTLV-I-infected people in Jamaica, common variants in HLA Class I genes were associated with a significantly increased risk of adult T-cell leukemia/lymphoma (ATL) and with non-significantly increased levels of HTLV-I proviral load. Common HLA variants were not related to HTLV-associated myelopathy. In our historical HIV/AIDS pilot studies, progression of HIV/AIDS and HIV viral load were shown to be associated with variants in the CTLA4 gene. Among 1394 children born to HIV-infected women in Malawi, the likelihood of HIV transmission was increased nearly 3-fold for girls compared to boys, perhaps because boys developed partially effective immune responses to maternal lymphocytes that lacked Y chromosome-derived antigens. In the U.S. HIV/AIDS Cancer Match Study, men with AIDS had an increased risk of seminoma but not of non-seminoma germ cell tumor. The elevated seminoma risk declined in recent years as anti-HIV treatments were developed and used, suggesting that the elevated risk might have been related to impaired tumor immunosurveillance or to AIDS-related testicular atrophy.For HIV/AIDS lymphomas, an analysis of 179 incident lymphomas and matched controls among HIV-1-seropositive homosexual men in the Multicenter AIDS Cohort Study (MACS). Subjects were genotyped for single nucleotide polymorphisms (SNPs) in B-cell stimulatory (IL10, IL10RA,CXCL12, CCL5), allergy-related (IL13, IL4, IL4R) and inflammation-related (BCL6) genes. Compared to the high IL10 genotype -592CC, carriers of the IL10-592A allele were at lower risk of NHL, and the putative low-producer IL10 haplotype, -1082A/-819T/-592A was less frequent in cases than controls (16% vs 22%, P=0.03). None of other studied genes differed significantly between cases and controls. The Uganda HIV/AIDS Cancer Match Study demonstrated that record-linkage studies can be done in resource poor countries. It showed significant association of HIV/AIDS with Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer, Hodgkin lymphoma and squamous cell carcinoma of the conjunctiva in Africans with HIV/AIDS. In addition, suggestive associations between HIV/AIDS and lung cancer and kidney cancer were observed. These associations will be clarified in other international populations.Using samples from the KS clonality and gene expression study, we tested the hypothesis that whole KS cells can be transmitted sexually was examined in 25 women by looking for presence of Y-chromosome in KS tumor cells as compared to normal cells. None were positive. Data on human herpesvirus 8 load in peripheral blood has been analyzed and shown to be associated with KS progression and, to a lesser extent, with KS burden. Other correlates include low hemoglobin and low platelets.KSHV/HHV8 PCR testing of saliva and blood lymphocytes from the KSHV/HHV8 sickle cell study showed high frequency and levels of viral shedding. Shedding in saliva was associated with shedding in peripheral blood, in both fluids was associated with younger age and with drinking water from unclean surface water sources. KSHV/HHV8 molecular sequencing showed evidence for maternal and non-maternal (e.g., community) acquired KSHV infection in the child. Analysis of EBV shedding in saliva and peripheral blood showed that HHV8 and EBV shedding are correlated, but the frequency and levels are much higher for EBV.Methodological studies using statistical mixture models to identify cut-off points for HHV8 serological assays, which don't have a gold standard, incorporating co-variates have been completed. Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses